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Published on: March 21, 2021
Macrolides induce severe cardiotoxicity and developmental toxicity in zebrafish embryos
Zhaoyang Yan1, Xiaoyong Huang2, Yangzhouyun Xie3
1Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; National Center for Veterinary Drug Safety Evaluation, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Abstract:
Macrolide antibiotics (MALs) are widely used for both human and animal health. Most MALs and their metabolites transfer into aquatic organisms and environment resulting in violent consequences. Previous studies show that MALs cause cardiotoxicity in humans and mammals. However, the potential risk of these chemicals in aquatic organisms remains unclear. Here, we used zebrafish embryos as a model to evaluate the toxicity of MALs. Zebrafish embryos were exposed to four typical MALs including azithromycin (AZM), clarithromycin (CLR), tilmicosin (TMS) and tylosin (TYL) to study their cardiotoxicity. The heart rate of zebrafish embryos showed similar biphasic distribution in the presence of four MALs at 2 days post-fertilization (dpf). The heart rate increased significantly at low levels of MALs while decreased obviously at high levels. Subsequently, TMS was chose to study its acute toxicity and developmental toxicity, which caused pericardial edema and spinal curvature in zebrafish embryos at 4 dpf. Furthermore, we found that TMS triggered oxidative stress, with decreased SOD activities and increased MDA contents. Lastly, apoptosis was observed in zebrafish embryos under TMS treatment, with up-regulation of apoptosis associated genes such as p53, bcl 2, bax, caspase 3 and caspase 9, confirmed by increased protein expression based on Western blot analysis. Taken together, these data indicate that MALs can cause serious toxicity in the development of zebrafish. Great caution should be taken due to the huge consumption of MALs for food animal production and treatments with TMS for infections in aquaculture.
Insights
Macrolide antibiotics (MALs) pose risks to aquatic life. This study found MALs cause cardiotoxicity and developmental issues in zebrafish embryos, highlighting environmental concerns from widespread use in agriculture and medicine.
Area of Science:
- Environmental Toxicology
- Aquatic Pharmacology
- Developmental Biology
Background:
- Macrolide antibiotics (MALs) are extensively used in human and animal health.
- MALs and their metabolites contaminate aquatic environments, posing ecological risks.
- While MALs' cardiotoxicity in mammals is known, their impact on aquatic organisms is unclear.
Purpose of the Study:
- To assess the cardiotoxicity and developmental toxicity of four common MALs in zebrafish embryos.
- To investigate the mechanisms of toxicity, including oxidative stress and apoptosis.
Main Methods:
- Zebrafish embryos were exposed to azithromycin, clarithromycin, tilmicosin (TMS), and tylosin.
- Heart rate was monitored at 2 days post-fertilization.
- Acute and developmental toxicity of TMS were evaluated at 4 days post-fertilization.
- Oxidative stress markers (SOD, MDA) and apoptosis-related gene/protein expression (p53, bcl 2, bax, caspase 3, caspase 9) were analyzed.
Main Results:
- A biphasic effect on heart rate was observed: increased at low MAL concentrations and decreased at high concentrations.
- TMS exposure led to pericardial edema and spinal curvature in zebrafish embryos.
- TMS induced oxidative stress, evidenced by decreased SOD activity and increased MDA levels.
- TMS triggered apoptosis in zebrafish embryos, confirmed by upregulated apoptosis-related genes and proteins.
Conclusions:
- Macrolide antibiotics exhibit significant cardiotoxicity and developmental toxicity in zebrafish embryos.
- Oxidative stress and apoptosis are key mechanisms underlying MAL-induced toxicity.
- The widespread use of MALs, particularly in aquaculture, warrants caution due to potential adverse effects on aquatic ecosystems.
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